Skin-Integrated Wearable Systems and Implantable Biosensors: A Comprehensive Review
, Ana I. Barbosa 1,2, Rita Rebelo 1,2, Il Keun Kwon 1, Rui L. Reis 1,2,3 and Vitor M. Correlo 1,2,*Round 1
Reviewer 1 Report
The review by Daniela Rodrigues et al., describes some challenges for implantable biosensor devices and concomitant strategies to overcome them.
In general, I urge the authors to revise the English manuscript as well as the references format, particularly in the text.
In addition, and specifically, I kindly request the authors to address my following concerns:
Line 33 – A biosensor is not necessarily a compact device. Please re-write.
Line 38 –Confusing sentence: “The transducer, in the other hand, as dependent of the resulting type of physiological change from the sensing event can be based on electrochemical, optical, calorimetric or acoustic transduction methods (Figure 1 (a)).” Revise and now reads as - a transducer depends on transduction methods.
The authors refer to bio-device, biosensor, transducer, medical devices, physical transduction element, etc.. which makes following the text a bit difficult. Other example that need to be rewritten is in Line 53: “In those medical devices...” what medical devices?
Line 60: Intimate way?
Line 74: The argument is incomplete in the sentence: “Biosensors generally consist of three fundamental components: i) the detector, to detect the stimulus or the biological component; ii) the transducer, to permute the stimulus in an output signal; and iii) the signal processing system, to process the output signal in an appropriate form. “
The authors need to include the signal to noise ratio and concomitant electrochemical noise as this is key for detection purposes for both biosensors discussed and implantable devices. References addressing this should be inserted. Such as:
- Kozai, T., Langhals, N., Patel, P. et al. Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces. Nature Mater 11, 1065–1073 (2012) and
- Rocha, P., Schlett, P., Kintzel, U. et al. Electrochemical noise and impedance of Au electrode/electrolyte interfaces enabling extracellular detection of glioma cell populations. Sci Rep 6, 34843 (2016).
Line 92. Please revise English.
Line 93: What stimulus? Please revise English.
Line 108: Double…See line 31.
127 This section is incomplete and vague. Please note that cell-based biosensors can also rely, simply, on a conducting electrode in close contact with cells. Intracellular and extracellular recordings are approached by the authors in this section. Yet, little explanation is provided. I recommend the authors to extend their explanation on topics such as limitations for extracellular recordings, where the actual measured signal (extracellularly) have an amplitude of about 0.1–1 % of the actual electrical pulses generated at the cell membrane (intracellularly). Also, please explain that this attenuation is a result of the poor cell coupling to the extracellular electrode due to a cleft with a typical thickness of 40–100 nm. – this by itself has a resistive effect in the propagation of the biosignals. In addition, and critically, SNR and electrochemical stability needs to be addressed. I recommend the authors to revise, accordingly, this section.
- Be specific. Sentences such as “can be used over long periods of time” should be avoided.
- They gain over cells?
- True. But what mechanical force and why? There are numerous articles and numbers that the authors can use and reference.
- Typo
- Would be nice to have reference for each.
- Who are “They…..”? What do the author mean by nerve stimulation. Electrical, chemical, both?
- Check English.
- Considered and well-studied?
- Revise English. And please specify what polymer substrates.
- Revise sentences like “small regions..” such as ? what do you mean by small? nm? um? mm? cm?, and “..those with modest curvature..”? what does modest mean?
- power densities such as?
- Low frequencies are a challenge to harvest and recent technologies are emerging to face this problem. The authors should mention this and proper reference it.
Author Response
#Response to Reviewer 1 comments
The review by Daniela Rodrigues et al., describes some challenges for implantable biosensor devices and concomitant strategies to overcome them.
In general, I urge the authors to revise the English manuscript as well as the references format, particularly in the text.
In addition, and specifically, I kindly request the authors to address my following concerns:
Line 33 – A biosensor is not necessarily a compact device. Please re-write.
Answer: Thank you for your comment. The reviewer is right. So, the word “compact” was deleted from the text.
Line 38 –Confusing sentence: “The transducer, in the other hand, as dependent of the resulting type of physiological change from the sensing event can be based on electrochemical, optical, calorimetric or acoustic transduction methods (Figure 1 (a)).” Revise and now reads as - a transducer depends on transduction methods.
Answer: Thank you for your comment. The sentence was modified for a better clarification: “A transducer depends on transduction methods, like electrochemical, optical, calorimetric or acoustic (…)”.
The authors refer to bio-device, biosensor, transducer, medical devices, physical transduction element, etc.. which makes following the text a bit difficult. Other example that need to be rewritten is in Line 53: “In those medical devices...” what medical devices?
Answer: Thank you for your comment. The authors kept the word biosensor for a more specific term, and medical device for more general terms, bio-device was eliminated and transducer and physical transducer element are not synonyms of biosensor, so they were kept when necessary.
The example in line 53 has been changed to the following:
Therefore, several studies have been made in researching and developing bio-integrated and implantable medical devices. In these devices, the most often monitored vital signs are heart electrical signals, blood pressure, pulse rate, blood glucose level, and respiration efficacy. [4]
Line 60: Intimate way?
Answer: Thank you for your comment. The word “intimate” was deleted from the text, in order to avoid misunderstandings.
Line 74: The argument is incomplete in the sentence: “Biosensors generally consist of three fundamental components: i) the detector, to detect the stimulus or the biological component; ii) the transducer, to permute the stimulus in an output signal; and iii) the signal processing system, to process the output signal in an appropriate form. “
The authors need to include the signal to noise ratio and concomitant electrochemical noise as this is key for detection purposes for both biosensors discussed and implantable devices. References addressing this should be inserted. Such as:
- Kozai, T., Langhals, N., Patel, P. et al. Ultrasmall implantable composite microelectrodes with bioactive surfaces for chronic neural interfaces. Nature Mater 11, 1065–1073 (2012) and
- Rocha, P., Schlett, P., Kintzel, U. et al. Electrochemical noise and impedance of Au electrode/electrolyte interfaces enabling extracellular detection of glioma cell populations. Sci Rep 6, 34843 (2016).
Answer: Thank you for your comment. Section 2 was fully revised and shortened by other reviewer suggestion. However, the reference and a small paragraph mentioning the importance of signal to noise ratio in electrochemical systems was added, as well as the references.
Line 92. Please revise English.
Answer: Thank you for your comment. The whole section was shortened and revised by suggestion of a different reviewer.
Line 93: What stimulus? Please revise English.
Answer: Thank you for your comment. The whole section was shortened and revised by suggestion of a different reviewer.
Line 108: Double…See line 31.
Answer: Thank you for your comment. The reviewer is right. The duplicate was deleted. The whole section was shortened and revised by suggestion of a different reviewer.
127 This section is incomplete and vague. Please note that cell-based biosensors can also rely, simply, on a conducting electrode in close contact with cells. Intracellular and extracellular recordings are approached by the authors in this section. Yet, little explanation is provided. I recommend the authors to extend their explanation on topics such as limitations for extracellular recordings, where the actual measured signal (extracellularly) have an amplitude of about 0.1–1 % of the actual electrical pulses generated at the cell membrane (intracellularly). Also, please explain that this attenuation is a result of the poor cell coupling to the extracellular electrode due to a cleft with a typical thickness of 40–100 nm. – this by itself has a resistive effect in the propagation of the biosignals. In addition, and critically, SNR and electrochemical stability needs to be addressed. I recommend the authors to revise, accordingly, this section.
Answer: Thank you for your comment. The whole section was shortened and revised by suggestion of a different reviewer.
- Be specific. Sentences such as “can be used over long periods of time” should be avoided.
Answer: Thank you for your comment. The whole section was shortened and revised by suggestion of a different reviewer.
- They gain over cells?
Answer: Thank you for your comment. The whole section was shortened and revised by suggestion of a different reviewer.
- True. But what mechanical force and why? There are numerous articles and numbers that the authors can use and reference.
Answer: Thank you for your comment. The whole section was shortened and revised by suggestion of a different reviewer.
- Typo
Answer: Thank you for your comment. The whole section was shortened and revised by suggestion of a different reviewer.
- Would be nice to have reference for each.
Answer: Thank you for your comment. The whole section 2 was shortened and revised by suggestion of a different reviewer, therefore the sentence no longer exists.
- Who are “They…..”? What do the author mean by nerve stimulation. Electrical, chemical, both?
Answer: Thank you for your comment. The sentence was reformulated for a better understanding: “Implantable biosensors have several advantages over other monitoring devices, since they can monitor biological metabolites, nerve electrical stimulation, (….)”.
- Check English.
Answer: Thank you for your comment. Sentence was re-written.
- Considered and well-studied?
Answer: Thank you for your comment. The sentence was reformulated: “The final shape and dimensions of the implantable biosensor must be biocompatible and well tolerated by the host, in order to avoid toxicity and chronic inflammation. [50]”.
- Revise English. And please specify what polymer substrates.
Answer: Thank you for your comment. The paragraph was revised and polymer substrates were specified.
- Revise sentences like “small regions..” such as ? what do you mean by small? nm? um? mm? cm?, and “..those with modest curvature..”? what does modest mean?
Answer: Thank you for your comment. The paragraph was revised and reformulated.
- power densities such as?
Answer: Thank you for your comment. The sentence referred to light power densities. It was clarified in the manuscript.
- Low frequencies are a challenge to harvest and recent technologies are emerging to face this problem. The authors should mention this and proper reference it.
Answer: Thank you for your comment. This information was mentioned and referenced in the manuscript.
Reviewer 2 Report
The manuscript is devoted to a highly interesting research topic providing a comprehensive view that includes each one of the elements involved in the development of wearable and implantable devices. The authors have done an excellent work compiling such extensive and multidisciplinary information to offer other researchers a valuable introduction to the field. The review is in general nicely written, although some sections should be revised to avoid some grammar/misspelling errors and to improve the understanding of some sentences.
In my opinion, although the review is of high interest, some changes should be made to improve its quality. First, section 2 “Biosensors overview” is far too long and not needed in a "Biosensors" journal. It can be shortened to a one single paragraph. Similarly, Figure 1 is not really required, or at least, a version avoiding duplication of information would be more appropriate. Same for Figure 2 and Figure 3.
If a simplified version of the section on the types of transduction is included, the authors should not forget about impedimetric biosensors in the electrochemical section ones (lines 203-206).
Lines 206-207: not all electrochemical sensors include three electrodes.
Section 3.1 on wearable biosensors includes some paragraphs, such as that from line 356 to line 393, that are too descriptive. Comparison of the discussed examples, highlighting the key aspects of each one, would provide more valuable and helpful information to the reader. Due to the recent high interest in sensing sweat, this same section might be improved by describing the different ways to obtain/extract sweat, such as iontophoresis.
Some examples of grammar/misspelling errors:
- line 35: “this bio-device comprise” should be “this bio-device comprises”
- lines 232-233: “the interaction between the target analyte and the immobilized molecule on the sensor surface produce” should be “the interaction between the target analyte and the immobilized molecule on the sensor surface produces”
- line 330: “of accommodate body movements” should be “of accommodating body movements”
- line 358: “can be find” should be “can be found”
- line 413: “Current efforts and challenges are resided” should be “Current efforts and challenges reside”
-line 472: “for devices achieve” should be “for devices to achieve”
- lines 509-510: “which acts either as physical scaffold and either an essential modulator” should be “which acts either as physical scaffold or essential modulator”
- line 555: “a novel polymer coating basing on” should be “a novel polymer coating based on”
- line 710: “also is required” should be “is also required”
Some examples of sentences difficult to understand:
- lines 328-330: “Flexible and stretchable electronic devices are usually built on substrates that reflect the flexibility and stretchability of the human skin and subsequently, involve a choice of a wide range of device and materials technologies.”
- lines 483-486: “Miniaturization can be reached either through miniaturization of sensing electrodes and elements and either miniaturization of driving electronics for power generation, data communication and their subsequent integration/packaging.”
- lines 707-709: “Advances on implantable medical devices used for sensing and stimulation are demanding in order to raise the complexity and length of follow-up observations, better methods to transmit the collected data obtained from the sensing.”
Please make sure all abbreviations are introduced the first time they appear, e.g. FBR in line 64.
Author Response
#Response to Reviewer 2 comments
The manuscript is devoted to a highly interesting research topic providing a comprehensive view that includes each one of the elements involved in the development of wearable and implantable devices. The authors have done an excellent work compiling such extensive and multidisciplinary information to offer other researchers a valuable introduction to the field. The review is in general nicely written, although some sections should be revised to avoid some grammar/misspelling errors and to improve the understanding of some sentences.
Comment 1. In my opinion, although the review is of high interest, some changes should be made to improve its quality. First, section 2 “Biosensors overview” is far too long and not needed in a "Biosensors" journal. It can be shortened to a one single paragraph. Similarly, Figure 1 is not really required, or at least, a version avoiding duplication of information would be more appropriate. Same for Figure 2 and Figure 3.
If a simplified version of the section on the types of transduction is included, the authors should not forget about impedimetric biosensors in the electrochemical section ones (lines 203-206).
Answer: Thank you for your comment. The section 2 of the review was shortened and other reviews that explore the topics were referenced in case the reader needs a more detailed information. Figure 1 was simplified and Figure 4 eliminated. Impedimetric biosensors concept was added to the text.
Comment 2: Lines 206-207: not all electrochemical sensors include three electrodes.
Answer: Thank you for your comment. The sentence was modified as follow: “Electrochemical biosensors are commonly composed by three electrodes: a reference electrode, a working electrode and a counter electrode, although they can be composed by only two or more than three”
Comment 3: Section 3.1 on wearable biosensors includes some paragraphs, such as that from line 356 to line 393, that are too descriptive. Comparison of the discussed examples, highlighting the key aspects of each one, would provide more valuable and helpful information to the reader. Due to the recent high interest in sensing sweat, this same section might be improved by describing the different ways to obtain/extract sweat, such as iontophoresis.
Answer: Thank you for your comment.
The following paragraphs were added to the text for discussion, comparison and key aspects emphasis.
“PDMS is a common material to produce flexible substrates in skin wearable sensors due to its chemical properties, biological compatibility, transparency, and good thermal stability, and especially its adhesion and non-adhesion areas that are clearly visible under UV light and can be easily adhered to the surface of electronic materials.[5]”
Nanomaterials such as SWCNTs, VACNTs, rGO, nanomembranes are commonly used in wearable skin sensors, since they can higly improve the specific signal over the background noise characteristic of human fluids.
“Also, finding ways to capture and store the sweat in a controlled fashion is important for the further development of skin wearable biosensors. Some studies have reported hydrogels loaded with acetylcholine and iontophoretic induce local sweat accumulation for further analysis.[1] Alternative approaches rely on sudomotor axon reflex sweating produced via iontophoresis of a nicotinic agonist using a wearable iontophoretic electrode.[2][3]”
Some examples of grammar/misspelling errors:
- line 35: “this bio-device comprise” should be “this bio-device comprises”
- lines 232-233: “the interaction between the target analyte and the immobilized molecule on the sensor surface produce” should be “the interaction between the target analyte and the immobilized molecule on the sensor surface produces”
- line 330: “of accommodate body movements” should be “of accommodating body movements”
- line 358: “can be find” should be “can be found”
- line 413: “Current efforts and challenges are resided” should be “Current efforts and challenges reside”
-line 472: “for devices achieve” should be “for devices to achieve”
- lines 509-510: “which acts either as physical scaffold and either an essential modulator” should be “which acts either as physical scaffold or essential modulator”
- line 555: “a novel polymer coating basing on” should be “a novel polymer coating based on”
- line 710: “also is required” should be “is also required”
Answer: Thank you for pointing out the grammar/misspelling errors. They have been all corrected in the revised version of the manuscript.
Some examples of sentences difficult to understand:
- lines 328-330: “Flexible and stretchable electronic devices are usually built on substrates that reflect the flexibility and stretchability of the human skin and subsequently, involve a choice of a wide range of device and materials technologies.”
- lines 483-486: “Miniaturization can be reached either through miniaturization of sensing electrodes and elements and either miniaturization of driving electronics for power generation, data communication and their subsequent integration/packaging.”
- lines 707-709: “Advances on implantable medical devices used for sensing and stimulation are demanding in order to raise the complexity and length of follow-up observations, better methods to transmit the collected data obtained from the sensing.”
Answer: Thank you for your comment. The mentioned sentences were re-written as follows, and added to the revised text.
“Flexible and stretchable electronic devices are usually built on substrates that reflect the flexibility and stretchability of the human skin and subsequently. These substrates are engineered using innumerous fabrication technologies, and materials blends in order to achieve the desired properties.”
“Miniaturization is achieved through size reduction of sensing electrodes, driving electronics for power generation, data communication and their subsequent integration/packaging.”
“Advances on implantable medical devices are demanding since the methods to translate the follow-up observations are time consuming and complex. Better methods to transmit the collected data obtained are urging for further developments in implantable devices.”
Please make sure all abbreviations are introduced the first time they appear, e.g. FBR in line 64.
Answer: Thank you for your comment. The abbreviations have been double checked through the manuscript in the revised version.
Reviewer 3 Report
This review paper introduces comprehensive review on skin-integrated wearable and implantable biosensors and those related systems. Unlike the other review papers on biosensors, this review paper also contains power supply and data communication as well as biosensor. Furthermore, they have introduced and organized the biosensors from concept to future research direction.
Comments:
- Figures are not sufficient. The author suggested to give more reference figures related to recent wearable and implantable biosensors.
- I recommend more references on wearable and implantable glucose sensor for continuous monitoring, “Science Advances 6 (2020) eaay5206”, “Proceedings of the National Academy of Sciences of the United States of America 108 (2011) 13399-13403”, “Biosensors and Bioelectronics 117 (2018) 267-275”
- Transducing materials are very important in the case of biosensor’s performance. This review lacks transducing materials description. The author suggested to provide a brief introduction of the transducing materials in section 2.
- The sub-section heading “bio-integrated wearable biosensor” is necessary to be changed into “skin-integrated wearable biosensor”.
- The sub-sections such as 3.2.2 power supply and 3.2.3 data communication are also related to skin-integrated wearable sensor. The various wearable biosensor also has similar issue regarding integration with power supplying and signal and data processing systems. I recommend those sections are changed into 3.3 and 3.4. Those sections should cover not only implantable sensor part, but also wearable sensor part.
- Section 3.1 and 3.2 contain various research fields of biosensors. Thus, Bio-integrated wearable biosensors and implantable sensors section should be classified into more specified sub-section. e.g.) 3.1 skin-integrated wearable sensor is composed of 3.1.1 sweat sensor, 3.1.2 bio-potential sensor, and 3.1.3 tear sensor. 3.2 implantable sensor is composed of 3.2.1 glucose sensor, 3.2.2 blood pressure sensor, and 3.2.3 bio-potential sensor.
- Figure 3 looks confusing. The author should provide more meaningful figures to make it understandable for the readership. All figures texts are blur, and figure resolutions are also not enough. They need to be improved for better understanding.
- In conclusion, the conclusion is not summarized well, and future directions are not described well.
Author Response
#Response to Reviewer 3 comments
This review paper introduces comprehensive review on skin-integrated wearable and implantable biosensors and those related systems. Unlike the other review papers on biosensors, this review paper also contains power supply and data communication as well as biosensor. Furthermore, they have introduced and organized the biosensors from concept to future research direction.
Comments:
- Figures are not sufficient. The author suggested to give more reference figures related to recent wearable and implantable biosensors.
Answer: Thank you for your comment. More figures were added related to wearable and implantable biosensors.
- I recommend more references on wearable and implantable glucose sensor for continuous monitoring, “Science Advances 6 (2020) eaay5206”, “Proceedings of the National Academy of Sciences of the United States of America 108 (2011) 13399-13403”, “Biosensors and Bioelectronics 117 (2018) 267-275”
Answer: Thank you for your suggestions. The references were added.
- Transducing materials are very important in the case of biosensor’s performance. This review lacks transducing materials description. The author suggested to provide a brief introduction of the transducing materials in section 2.
Answer: Thank you for your suggestions. Section 2 has been revised and shortened, to be only a small overview by suggestion of other reviewer.
- The sub-section heading “bio-integrated wearable biosensor” is necessary to be changed into “skin-integrated wearable biosensor”.
Answer: Thank you for your comment. The sub-section heading was changed.
- The sub-sections such as 3.2.2 power supply and 3.2.3 data communication are also related to skin-integrated wearable sensor. The various wearable biosensor also has similar issue regarding integration with power supplying and signal and data processing systems. I recommend those sections are changed into 3.3 and 3.4. Those sections should cover not only implantable sensor part, but also wearable sensor part.
Answer: Thank you for your comment. The sub-sections were modified.
- Section 3.1 and 3.2 contain various research fields of biosensors. Thus, Bio-integrated wearable biosensors and implantable sensors section should be classified into more specified sub-section. e.g.) 3.1 skin-integrated wearable sensor is composed of 3.1.1 sweat sensor, 3.1.2 bio-potential sensor, and 3.1.3 tear sensor. 3.2 implantable sensor is composed of 3.2.1 glucose sensor, 3.2.2 blood pressure sensor, and 3.2.3 bio-potential sensor.
Answer: Thank you for your comment. The sections were classified into more specific sub-sections, as suggested.
- Figure 3 looks confusing. The author should provide more meaningful figures to make it understandable for the readership. All figures texts are blur, and figure resolutions are also not enough. They need to be improved for better understanding.
Answer: Thank you for your comment. Figures 2,3 and 4 were removed from the text for suggestion of another reviewer. The resolution of the other figures was improved.
- In conclusion, the conclusion is not summarized well, and future directions are not described well.
Answer: Thank you for your comment. All the conclusion was rewritten, in order to be more clear and summarized, and future directions were added.
Round 2
Reviewer 1 Report
N/A
Reviewer 3 Report
All the comments were well addressed. It is now acceptable.
